The overall goal of this research project is to understand, on a fundamental level, in both molecular and quantitative terms, how eukaryotic cells divide, move, and adapt to their environment. These are inherently systems-level problems, for which we plan to take a fully integrated approach that combines whole-cell quantitative observation and mathematical modeling with traditional structure-function analysis that illuminates molecular mechanisms. In addition to the goal of uncovering fundamental principles, we will actively seek opportunities to apply new insights from basic research to the improvement of human health. The work to be supported by this MIRA grant falls into three general areas that have been funded by three independent NIGMS grants: I) Asymmetric cell division is a major developmental mechanism in the generation of diverse cell types or fates through cell division and is frequently used by stem cells to satisfy both self-renewal and differentiation. Our work will be focused on using the budding yeast as the model system to understand how protein and lipid components of the plasma membrane self-organize to drive cellular symmetry breaking and the establishment of cell polarity; and how the axis of cell polarity directs the segregation of molecular determinants that specify the replicative age of the two progeny cells of each cell division. In particular, we will unravel the role of ER and mitochondria in the consolidation and segregation of proteome damage, and test the hypothesis that this function is directly linked to an asymmetry in mitochondria biogenesis during asymmetric cell division. This research is envisioned to be expanded to mammalian stem cells in the future. II) Cell motility is a critical process required for the development and physiology f animal organisms that also depends on cell polarity and dynamic assembly of the cytoskeleton. Part of the proposed work will be conducted as a PO1 collaborative effort with several labs with leading expertise in electron cryo-microscopy, actin biochemistry, and mathematical modeling of cell dynamics and mechanics. My group will use mouse genetic techniques, primary cell culture and live imaging to probe the role of dendritic actin nucleation in cell motility. Our collective gal is to achieve a quantitative understanding of how actin polymerization and filament organization produce the force driving directional protrusion of the leading edge. A second goal is to use primary motile cells from mice to gain insights into the diversity and plasticity of cell motility mechanisms in different mechanical and geometrical environments. III) Evolvability is the fundamental capacity of biological systems that enables cells and organisms to undergo genetic changes to adapt to internal or environmental perturbations. Evolvability on the cellular level, th focus of our research, also underlies the ability of cancer cells and pathogenic microbes to elude the host immune system or become resistant to therapeutic treatments. Our proposed work is designed to decipher how chromosome copy number variation, or aneuploidy, as a result of chromosome instability produces dramatic phenotypic change and drives rapid cellular adaptation. We will also investigate general defects caused by chromosome dosage imbalance and how such deficiencies may be exploited for anti-cancer treatment.